This study will determine whether antagonists of collagen metabolism can ameliorate tissue fibrosis induced by ionizing radiation or by antineoplastic drugs. The initial target organ is the irradiated rat lung, and the initial collagen antagonists is D-penicillamine. Lung histopathology will be correlated with chest radiographs, and with biochemical analysis of lung collagen synthesis and content. Functional endpoints include survival, compliance, arterial perfusion and ventilation. We have found that peniciliamine reduces fibrosis in both the lung and skin of rats sacrificed three or six months after 2500 rads of gamma rays. We propose to extend the observation period to nine and twelve months, and to determine whether penicillamine actually prevents fibrosis, or simply delays (or precipitates) its onset upon drug withdrawal. Subsequent experiments will expand our present model to more clinically relevant conditions i.e. fractionated irradiation and tumor-bearing lung; and to a second therapeutic moduality, bleomycin (alone and in combination with radiation). Finally, we propose to investigate another collagen antagonist, cis-hydroxyproline, and another critical organ, the liver. The project may identify a strategy to increase normal tissue tolerance to radio- and/or chemotherapy. The ultimate objective of this study is to accumulate sufficient experimental data to justify clinical trials with penicillamine. If collagen antagonists can, in fact, inhibit chronic fibrotic reactions in dose-limiting organs, the cancer therapist may be able to be more aggressive in the treatment of neoplastic disease.